Post-translational regulation of interleukin 1 beta secretion

Abstract

In view of the key role played by interleukin 1 (IL-1) beta in inflammation, its production is likely to be precisely regulated. Previous studies have shown that IL-1 beta biosynthesis is controlled at the transcriptional and translational levels. We have investigated whether post-translational events also play a role in regulating the production of bioactive IL-1 beta. IL-1 beta, which lacks a signal sequence, is released by activated monocytes through a novel pathway of secretion, alternative to the classical endoplasmic reticulum-Golgi route. Secretion of mature 17 kDA IL-1 beta is increased when pulse-labelled activated monocytes are chased in the presence of heat-aggregated immunoglobulins or of various drugs. Febrile temperatures inhibit secretion of mature IL-1 beta, but only reduce its synthesis: treatment with cycloheximide restores secretion. Processing of the 33 kDa precursor to the 17 kDa mature molecule is inhibited when the external pH is 8 or higher: under these conditions, release of unprocessed, biologically inactive 33 kDa IL-1 beta is observed. Thus, secretion of IL-1 beta is regulated by post-translational mechanisms which operate at the level of both proteolytic processing and extracellular export.